LA JOLLA, Calif. — As her father lay dying of sepsis, Janelle Ayres spent nine agonizing days at his bedside. When he didn’t beat the virulent bloodstream infection, she grieved. And then she got frustrated. She knew there had to be a better way to help patients like her dad.
In fact, she was working on one in her lab.
Ayres, a hard-charging physiologist who has unapologetically decorated her lab with bright touches of hot pink, is intent on upending our most fundamental understanding of how the human body fights disease.
Scientists have focused for decades on how the immune system battles pathogens. Ayres believes other elements of our physiology are at least as important — so she’s hunting for the beneficial bacteria that seem to help some patients maintain a healthy appetite and repair damaged tissue even during bouts of serious disease.
If she can find them — and she’s already begun to do so — she believes she can develop drugs that will boost those qualities in patients who lack them and help keep people alive through battles with sepsis, malaria, cholera, and a host of other diseases.
Her approach, in a nutshell: Stop worrying so much about fighting infections. Instead, help the body tolerate them.
And no, she’s not spouting some New Age California mumbo jumbo about letting the body heal itself. An associate professor at the Salk Institute in the heart of San Diego’s booming biotech beach, Ayres is harnessing all manner of high-tech tools from the fields of microbiomics, genetics, and immunology — and looking to a menagerie of animals — to sort out why some individuals tolerate infection so much better than others.
It’s work that’s desperately needed, Ayres said, as it becomes ever more clear that our standard approach to fighting infection using antibiotics and antivirals is hopelessly inadequate. The drugs don’t work for all diseases, they kill off good bacteria along with bad — and their wanton use is contributing to the rise of antibiotic resistant bacteria, or “superbugs,” which terrify disease experts because there are few ways to stop them.
Ayres’s father, Robert Lamberton, developed sepsis after a routine gallbladder surgery in 2015. Battling to fight the infection in the ICU, the hospital used an arsenal of antibiotics.
“We’re focused only on making new antibiotics,” Ayres said. “And that’s an arms race that we’re never going to win.”
Ayres’s journey started with thousands of sick, mutant flies. It was about 10 years ago, in biologist David Schneider’s lab at Stanford, where Ayres was a grad student. She infected more than 10,000 flies, carrying various genetic mutations, with listeria. “I injured my hand because I had to inject so many flies,” she recalled.
While many immunologists would look for very specific immune responses, Ayres asked a simpler, but perhaps more important, question: Which flies survived?
By comparing the mutants that died quickly against the survivors, she found specific sets of genes that played roles in preventing, curbing, and even repairing damage from the listeria infection — regardless of the level of bacteria in the flies’ bodies.
Schneider and Ayres described the response of the surviving flies as tolerance. They went on to propose that the immune response to pathogens wasn’t the whole story, and that tolerance — a body’s ability to minimize damage while infected — may play a key role as well. Ayres has since gone on to call what she studies the “tolerance defense system.”
“We were telling the field of immunology, ‘You need a perspective shift,’” Ayres said.
Immunologists were not impressed.
They weren’t happy to see the longtime focus on the immune system challenged, said Schneider, who chairs the Stanford University School of Medicine’s department of microbiology and immunology. And they hated the term “tolerance” because it has a number of specific technical meanings within their field.
“Every time we used that word, immunologists would jump down our throats and complain that we couldn’t take their word,” Schneider said.
It seemed a petty and silly disagreement, he said, given that plant biologists have used the word tolerance for more than a century to describe infected plants that nonetheless stay healthy enough to bear fruit. “We were not stealing their word,” he said.
“We’re focused only on making new antibiotics. And that’s an arms race that we’re never going to win.”
Despite the cold reception, the idea immediately caught the eye of one of the nation’s most renowned and creative immunologists: Ruslan Medzhitov, who has scooped up nearly every recent major prize for biology and who many think was unfairly overlooked for the 2011 Nobel Prize for his co-discovery of Toll-like receptors, pattern recognition molecules key to the immune system.
Medzhitov had been frustrated for years by a finding he could not explain. In experiment after experiment, he noted that infected animals differed wildly in their survival rates — and it didn’t seem to matter how many pathogens or disease-causing microbes they carried. If killing microbes was all that mattered, he said, this differential survival of infected animals made no sense at all.
“All the standard thinking about how the immune system works,” he said, “was clearly inefficient.”
So when he first read papers by Ayres and Schneider — and work by Andrew Read and Lars Raberg at Penn State — he became convinced that tolerance was the key issue immunologists had long overlooked.
“I was immediately hooked on the idea,” he said. “It sounded so logical and biologically satisfying.”
For his part, Schneider describes the current focus on killing microbes as “a really violent and militaristic approach.”
“No one says, ‘Why can’t we just live together?’” he said.
That’s just what Ayres is asking in her lab.
A trailblazer in sparkly loafers
Ayres may have gravitated to this trailblazing field because she’s something of an iconoclast herself. The product of a humble family — her father a farm-raised German immigrant, her mother a bookkeeper — Ayres is the only one of three siblings who’s a scientist. “My family has always been very proud of me,” she said. “But they’ve never understood what I do.”
Ayres’s lab at Salk, which happens to be all female, is decidedly pink and glittery, down to the lab stepstool. Scientists wear hot pink rubber gloves. Lab hoodies are pink with “Wolf Pack” printed on the back. Bottles of champagne — yes, it’s also pink — from various lab celebrations line a shelf.
Sitting quietly on another shelf: Science Barbie. “Her skirt’s too short, but she does have closed-toed shoes and goggles,” quipped Ayres.
Ayres, who is in her 30s, makes frequent appearances at area high schools — teaming her white lab coat with glamorous eye shadow and sparkly loafers to send a strong message that female scientists can be great researchers and also be themselves. Ayres’s lab has been all female for four years by happenstance, she said. Her first male postdoc will join this fall, she said, adding dryly: “I hope he likes pink.”
Those who know Ayres attribute her success in part to her broad curiosity. She reads widely, and far outside her discipline.
In fact, it was a 19th-century paper on plants that remained healthy despite being infected with leaf rust that helped inform Ayre’s thinking on tolerance. “It had never been looked at in animals, never described in animals,” she said, speaking with her characteristic rapid-fire enthusiasm. “That’s why you should always read papers outside your bubble.”
(She’s also fascinated with Typhoid Mary, the chef who sickened dozens and killed three in the early 1900s in New York, but somehow tolerated her own infection.)
Taking a page from her former adviser, Ayres uses math, evolutionary theory, and ecology in her work and is always gobbling up new papers on interesting animals — recently it’s been ants and hagfish — that might shed light on the phenomenon she’s studying and the bigger picture outside the Petri dish. “I just texted Janelle about naked mole rats,” Schneider said. “I can’t look at another T cell.”
Plainspoken and direct, Ayres could be classified as a workaholic. Other than spending time with her husband and beloved golden retriever — whom she named Hans Ferdinand after her father’s original German name — Ayres admits to spending most of her time immersed in work.
“If you’re a scientist, it’s a lifestyle, not a job,” she said.
“If you’re a scientist, it’s a lifestyle, not a job.”
Not that she doesn’t have a sense of humor.
On a recent day, she led her lab mates on a wild chase through the lab, the group shrieking and laughing as they searched for the source of a particularly foul smell. It turned out to be a beaker full of mystery bugs that someone had let sit too long.
Her team has also been waiting, unsuccessfully, for months for bacteria to grow on a doughnut they keep prominently displayed in the lab. (The wait has led to a lot of uneasy jokes about what could be in the doughnut to inhibit all microbial growth.)
Ayres said she feels extremely fortunate to be at the Salk, an iconic ocean-side collection of cement and teak buildings that, in the 1960s, was among the first science institutes to be built with literally no walls between labs. Ayres said it speeds up her work immensely to so easily work with colleagues who are experts on neuroscience and metabolism.
But the main reason for her success may be the work ethic she inherited from her father. Robert Lamberton was a jet mechanic who worked seven days a week, commuting several hours each day from his home in Livermore to the Rolls Royce plant in Oakland.
As a teen, Ayres scooped ice cream and stocked grocery store shelves while in high school. She earned a 4.0 grade point average at Berkeley even while commuting several hours each day and working full time in a lab. Her drive continued at Stanford, where she got her PhD in 2009. “She was commuting several hours a day and still getting so much done,” Schneider said. “She works incredibly hard.”
Like her dad, a Navy man and Vietnam vet who wasn’t above scrubbing the decks even after he rose through the ranks to run a jet engine test facility, Ayres is also willing to roll up her lab coat sleeves when needed.
“I’ll go collect mouse poo,” she said. “I’m not above that.”
Her work is getting notice: In 2014, Ayres was one of just 15 young scientists in the US to be named a Searle Scholar. The next year, the Pentagon’s Defense Advanced Research Projects Agency recognized her with a young faculty award. The two honors came with a combined $800,000 in research funding.
A war we can’t win
More than 700,000 deaths each year worldwide are attributed to infections that our current roster of drugs cannot beat back. The World Health Organization recently released a “most wanted” list of the world’s most dangerous superbugs.
The public health response, so far, has been to clamor for newer and more effective antibiotics. A public-private partnership in the US and UK, for instance, is investing tens of millions over the next three years in startups working on new drugs.
And last month, Democrats in both houses of Congress introduced a bill that included $2 billion to establish a prize fund specifically for new antibiotics.
All Ayres can do is sigh.
She understands bacteria deeply. She respects them and even loves them. And she knows they will always win.
Society needs drugs that don’t target bacteria, which can so quickly evolve to evade our best medicines, she argues.
Instead, she thinks we can harness those bacteria — even the ones normally classified as pathogens — to make new drugs that save lives by targeting an infected person’s tissues and organs. That would be an entirely new class of therapeutics, which could lessen our dependence on antibiotics and help save lives in cases, like her father’s, where antibiotics fail.
She’s had a tough time spreading her view. STAT contacted a number of experts in antibiotic resistance who said they did not know enough about the new area to comment.
Yet slowly, some researchers are starting to come around.
Inducing tolerance in a patient “is perhaps the missing but essential element to add to the current components of sepsis care and treatment,” three experts on sepsis — the bloodstream infection that killed Ayres’s father — wrote in a medical journal editorial last year.
The approach could also help with viral diseases like the flu. And it could also make a difference with cancer. As Schneider notes, tolerance seems to be an issue in the field: Some cancer patients survive despite large tumor loads, where others succumb to the smallest of tumors. Drugs that could help patients retain their appetites and strengthen bodies weakened by chemotherapy and radiation could potentially boost survival rates.
“It’s essentially a completely new class of drugs, a completely new therapeutic strategy,” said Medzhitov, who himself is heading a startup called Vendanta, which aims to hunt for new classes of microbial drugs to treat autoimmune and inflammatory diseases.
Ayres is not involved with that project. She’s been working furiously in her own lab, rolling out a series of studies that have found critical targets for new drugs. Her main focus: the trillions of bacteria — known collectively as the microbiome— that reside in our bodies but do not sicken us. Ayres suspects they might play a key role in the tolerance defense system.
“[Killing pathogens is] a really violent and militaristic approach. No one says, ‘Why can’t we just live together?’”
But if bacteria do help increase tolerance to disease, what strains are involved and what exactly are they doing?
Seeking an answer, Ayres and researchers Michelle Lee and Alexandria Palaferri Schieber collected mice from around the country and tested how they responded to pneumonia and intestinal infections caused by a type of salmonella. (Ayres is always eager to show visitors a small jar of mice innards she keeps in her lab.)
In this study, the mice were genetically identical, but because they had been raised in different environments, they had entirely different microbiomes. One group of mice did not suffer from muscle wasting despite having comparable levels of pathogens — suggesting that something in their microbiome was promoting tolerance.
When they compared the microbiomes of these tolerant mice to regular mice, they found only the tolerant mice carried a specific strain of E. coli, one Ayres calls a “superhero bug.” That strain, when given to regular mice, kept them from wasting as well.
Further study showed the E. coli was leaving the gut and migrating to fat tissue, where it was activating a part of the immune system called the inflammasome that can trigger inflammation to help fight microbes. In this case, the E. coli was using those same mechanisms to nourish muscles. Ayres is now looking for an analog in humans that might one day be used as a treatment for wasting.
In another study, Ayres found a bacterial protein called SlrP (pronounced “slurpee”) could keep mice from dying of salmonella infection. Mice infected with a mutant salmonella strain that did not include the protein ate less, lost weight, and died more quickly than mice infected with regular salmonella.
Ayres and researcher Sheila Rao found that the SlrP protein in wild salmonella blocked signals that the gut normally sends to the brain to tell it to stop eating — and helped keep the mice it had infected alive and eating well.
“Salmonella has actually evolved ways to keep us healthy,” Rao said. They have a vested interest in doing so: As long as we keep eating and moving about, the salmonella can continue to flourish and spread to other hosts.
Ayres hopes to use this insight to develop a SlrP-based drug that can increase appetite in the sick, or those undergoing chemotherapy.
Ayres is anxious to push forward the basic science on tolerance — and is convinced that it will lead to new cures. “I absolutely think these would have saved my dad,” she said.
It’s too late for Robert Lamberton. But it might not be too late for others.